Opioid dependence is a severe public health problem (Zweben J E, Payte J T. (1990) Methadone maintenance in the treatment of opioid dependence. A current perspective. Western Journal of Medicine. 152(5):588-99). Current efforts to taper individuals off opioid medications often lead to limited results due to a high relapse rate (Broers B, Gilner F, Dumont P, Mino A. (2000) Inpatient opiate detoxification in Geneva: follow-up at 1 and 6 months. Drug Alcohol Depend. 58: 85-92; Gossop M, Green L, Phillips G, Bradley B. (1989) Lapse, relapse and survival among opiate addicts after treatment. A prospective follow-up study. Br. J. Psychiatry. 154: 348-353) and troublesome subjective symptoms. Although substitution therapies with methadone for opioid dependence have been found to be effective, the relapse rates following discontinuation of methadone remain high, suggesting that substituting therapies might not be sufficient in the treatment of opioid dependence and addictive diseases (Bisaga A, Popik P. (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug Alcohol Depend. 59: 1-15).
Dextromethorphan (DM) is an effective and widely used antitussive drug. It is a dextrorotatory opioid derivative that does not act on opioid receptors but is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. DM may be useful in the treatment of opioid dependence, particularly as a means of reducing tolerance to methadone during replacement therapy. In animal models, NMDA antagonists modulate many effects of chronic administration of opioids. NMDA antagonists alleviate physical withdrawal syndrome, attenuate ongoing drug dependence, reduce the tolerance of opioid, and inhibit the reward dependence (Bisaga A, Popik P. (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug Alcohol Depend. 59: 1-15). Several studies have indicated that NMDA receptor antagonists reduce the development of tolerance to the analgesic effects of opiates (Herman B H, O'Brien C P. (1997) Clinical medication development for opiate addiction: focus on nonopioids and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention. Semin. Neurosci. 9: 158-172). Furthermore, by reducing the development of opioid tolerance, NMDA receptor antagonists could be particularly useful in methadone maintenance therapy because patients could be maintained at lower dosages, leading to fewer withdrawal symptoms when methadone therapy is terminated (Cornish J W et al. (2002) A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83).
NMDA receptor antagonists reduce the physical aspects of the expression of morphine dependence as measured by naloxone-precipitated withdrawal (Bristow L J, Hogg J E, Hutson P H. (1997) Competitive and glycine: NMDA receptor antagonists attenuate withdrawal-induced behaviours and increased hippocampal acetylcholine efflux in morphine-dependent rats. Neuropharmacology. 36: 241-250; Popik P, Danysz W. (1997) Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine. J. Pharmacol. Exp. Ther. 280: 854-865; Popik P, Mamczarz J, Fraczek M, Widla G, Hesselink M, Danysz W. (1998) Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists. Neuropharmacology. 37: 1033-1042) and may attenuate not only the physical but also affective and motivational components of abstinence states, as well as craving (Cornish J W et al. (2002) A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83). By reducing withdrawal symptoms, such medications should be beneficial for the patients during the acute detoxification phase of treatment for opioid dependence (Cornish J W et al. (2002) A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83).
NMDA antagonists have been shown in mice to inhibit morphine self-administration and to inhibit both the development and expression of morphine conditioned place preference (Popik P, Mamczarz J, Fraczek M, Widla G, Hesselink M, Danysz W. (1998) Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists. Neuropharmacology. 37: 1033-1042; Del Pozo E, Barrios M, Baeyens J M. (1996) The NMDA receptor antagonist dizocilpine (MK-801) stereoselectively inhibits morphine-induced place preference conditioning in mice. Psychopharmacology. 125: 209-213; Kim H, Jang C, Park W. (1996) Inhibition by MK-801 of morphineinduced conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice. Pharmacol. Biochem. Behav. 55: 11-17). These results suggest that DM could have clinical utilities in preventing the development and expression of conditioned drug-dependence effects in humans.
Chronic exposure to morphine results in a number of biochemical adaptations of the glutamatergic receptor system in the limbic system (Fitzgerald L W, Ortiz J, Hamedani A G, Nestler E J. (1996) Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J. Neurosci. 16: 274-282). Excitatory amino acids are involved in the mediation of many neurochemical and behavioral effects resulting from chronic exposure to abusing drugs, some of which can be prevented or reversed using glutamatergic antagonists (Inturrisi C E. (1997) Preclinical evidence for a role of glutamatergic systems in opioid tolerance and dependece. Semin. Neurosci. 9: 110-119). Furthermore, the continued self-administration of abusive drugs, including opioid, may result in an overstimulation of dopamine in the brain reward centers and an increased release of excitatory amino acids (including glutamate), leading to the development of tolerance and dependence which could be blocked by glutamate antagonists (Herman B H, O'Brien C P. (1997) Clinical medication development for opiate addiction: focus on nonopioids and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention. Semin. Neurosci. 9: 158-172).
In addition to the above-mentioned NMDA blocking effects, DM has been reported to afford neuroprotection on dopamine neurons in several inflammation-based animal Parkinson's disease models (Li G, Liu Y, Tzeng N S, Cui G, Block M L, Wilson B, Qin L, Wang T, Liu B, Liu J, Hong J S. (2005) Protective effect of dextromethorphan against endotoxic shock in mice. Biochemical Pharmacology. 69(2): 233-40; Liu Y, Qin L, Li G, Zhang W, An L, Liu B, Hong J S. (2003) Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. Journal of Pharmacology & Experimental Therapeutics. 305(1):212-8; Zhang W, Wang T, Qin L, Gao H M, Wilson B, Ali S F, Zhang W, Hong J S, Liu B. (2004) Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB Journal. 18(3): 589-91; Zhang W, Qin L, Wang T, Wei S J, Gao H M, Liu J, Wilson B, Liu B, Zhang W, Kim H C, Hong J S. (2005) 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB Journal. 19(3): 395-7). Zhang et al. (2004) obtained novel findings that 1-10 μM DM protected dopamine neurons against lipo-polysaccharide (LPS)-induced reduction of dopamine uptake in rat primary mixed mesencephalic neuron-glia cultures. Morphologically, in LPS-treated cultures, besides the reduction of an abundance of dopamine neurons, the dendrites of the remaining dopamine neurons were significantly less elaborative than those in the controls. In cultures pretreated with DM (10 μM) before LPS stimulation, dopamine neurons were significantly more numerous and the dendrites less affected. Significant neuroprotection was observed in cultures with DM added up to 60 minutes after the addition of LPS. Thus, DM significantly protects monoamine neurons not only with pretreatment but also with post-treatment (Zhang W, Wang T, Qin L, Gao H M, Wilson B, Ali S F, Zhang W, Hong J S, Liu B. (2004) Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB Journal. 18(3): 589-91). Animal studies using both LPS and MPTP PD models also show potent protective effect of DM (Zhang W, Wang T, Qin L, Gao H M, Wilson B, Ali S F, Zhang W, Hong J S, Liu B. (2004) Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB Journal. 18(3): 589-91).
The mechanism of the neuronprotective effect of DM is associated with the inhibition of microglia over-activation by inhibition of superoxide anion production from NADPH-oxidase, and this neuroprotective effect of DM is not associated with its NMDA receptor antagonist property. Zhang et al. (2005) examined several NMDA receptor antagonists, including MK801, AP5 and memantine. They found no correlation between the affinity of NMDA receptor antagonist activity and potency of the neuroprotective effect on dopamine neurons. On the contrary, a better correlation was observed between the anti-inflammatory potency and neuronprotection. These results suggest that the dopamine neuroprotection provided by DM in the inflammation-related neurodegenerative models is not mediated through the NMDA receptor. This conclusion is not in conflict with previous reports, indicating that NMDA receptor blockade is associated with the neuroprotective effects of DM in the acute glutamate-induced excitotoxicity models.
Opioid agonists have been reported to modulate the immune system through opioid receptors in the central nervous system (CNS). Direct actions of opiates on immune cells were observed in in vitro studies (Madden, J. J., W. L. Whaley, et al. (1998). Opiate binding sites in the cellular immune system: expression and regulation. J Neuroimmunol 83(1-2): 57-62). Opioid receptors, including μ3 and δ isoforms, were found in immune cells. Indirect actions of morphine also can be demonstrated in the immunological system. Morphine induces thymocyte apoptosis in vivo but not in vitro (Fuchs, B. A. and S. B. Pruett (1993). Morphine induces apoptosis in murine thymocytes in vivo but not in vitro: involvement of both opiate and glucocorticoid receptors. J Pharmacol Exp Ther 266(1): 417-23). Thymus hypoplasia was shown to be glucocorticoid (GC)-dependent (Sei, Y., K. Yoshimoto, et al. (1991). “Morphine-induced thymic hypoplasia is glucocorticoid-dependent.” J Immunol 146(1): 194-8). GC-dependent effects of morphine activate the hypothalamic-pituitary-adrenal (HPA) axis. The activation of the HPA axis increases the products of GC as potent immunomodulatory hormones (Freier, D. O. and B. A. Fuchs (1994). A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of natural killer cell activity. J Pharmacol Exp Ther 270(3): 1127-33; Mellon, R. D. and B. M. Bayer (1998). Role of central opioid receptor subtypes in morphine-induced alterations in peripheral lymphocyte activity. Brain Res 789(1): 56-67).
Based on the above-mentioned evidence, the Applicant hypothesize that DM add-on therapy to long-action methadone maintained treatment method for opioid dependence instead of opioid use. The optimal dose of DM for this kind of usage is not clear. Bisaga et al. reported the dosage of 375 mg/day DM for heroin addicts undergoing withdrawal. In Cornich's study, participants received doses of 120, 240, and 480 mg/day of DM in increasing order. DM at high doses caused mild elevations of heart rate, blood pressure, temperature, and plasma bromide (Cornish J W et al. (2002) A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83). Particularly among Hang Chinese in Taiwan, DM has been reported to have quite different dextromethorphan metabolic enzyme P450 2D6 from that of Western population (Yeh G C, Tao P L, Ho H O, Lee Y J, Chen J Y, Sheu M T. (2003) Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes. J. Biomed. Sci. 10: 552-564).
Bipolar disorder (BP), characterized by a dysregulation of mood, impulsivity, risky behavior and interpersonal problems, is a recurrent and often chronic psychiatric illness. According to World Health Organization (WHO), it is associated with functional impairment, elevated suicide rates and utilization of mental health systems. Two subtypes of bipolar disorder, including bipolar I (BP-I) and bipolar II (BP-II) have been emphasized (American Psychiatric Association, 2000). However, bipolar disorder is commonly under-recognized even in psychiatric settings, especially bipolar-II subtype. As many as 40% of patients with bipolar disorders are initially misdiagnosed, and it may take years before those patients receive correct diagnosis and appropriate treatment. The missed treatment likely plays a part in increasing risk for suicide, mania and chronic psychosocial suffering, adding further to the burden on both patients and society. Even when the patients receive correctly diagnosed, fewer than 50% patients are treated successfully (NIMH 2002), and 10-15% may eventually die as a result of suicide.
While the pharmacological guidelines for treatment are well established, treatment for bipolar disorder remains less than ideal. Most individuals still have breakthrough episodes or significant residual symptoms while on medication (NIMH 2002). In addition, functional deficits often remain even when patients are in remission (NIMH 2002). Because many patients with bipolar disorder remain symptomatic, even while fully adherent to their medication regimens, the need for greater understanding of the pathogenesis of this illness from the research on the pharmacological mechanisms of bipolar medications is all the more urgent. The major medication therapy of bipolar disorders is mood stabilizers, unless the pharmacology mechanisms are not clear yet. Recent researchers reported common neuroprotective effects of mood stabilizers, suggesting a role of brain cell dysfunction in bipolar disorder and the dysfunction may eventually cause neuron loss. Volumetric neuroimaging, now increasingly assessing potential involvement of different brain structures in mood regulation, could be applied to test neuroanatomical models of mood disorders. Imaging studies suggested that ongoing neuronal atrophy accompanies bipolar disorder. For instance, PET images of the cerebral blood flow and the rate of glucose metabolism regarding as brain activity detected the reduced activity in subgenual prefrontal cortex during bipolar depression. This decrement in activity was, in part, at least explained by a corresponding reduction of cortical volume, as same as magnetic resonance imaging demonstration of the mean grey matter volume. In bipolar disorder, abnormalities of the third ventricle, frontal lobe, cerebellum, and possibly the temporal lobe are also noted.
Furthermore, studies had shown the significantly higher interleukin-6, interleukin-8 and TNF-α levels in bipolar patients during manic and depressive episodes than normal controls (Kim, H. W., Rim, H. D., Kim, J. H., Lee, S. J. Alexithymia and Stress Response Patterns among Patients with Depressive Disorders in Korea. Psychiatry Investig. 2009; 6(1): 13-8; O'Brien, S. M., Scully, P., Scott, L. V., Dinan, T. G. Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord. 2006: 90(2-3): 263-7; Brietzke, E., Stertz, L., Fernandes, B. S., Kauer-Sant'anna, M., Mascarenhas, M., Escosteguy Vargas, A., Chies, J. A., Kapczinski, F. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord. 2009; 116(3): 214-7). In postmortem frontal cortex from bipolar disorder patients, the significantly higher protein and mRNA levels of IL-1β receptor and neuroinflammatory markers inducible nitric oxide synthase (iNOS) and c-fos were found (Rao, J. S., Harry, G. J., Rapoport, S. I., Kim, H. W. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol. Psychiatry. 2010; 15(4): 384-92). Taken together, the unbalance of immune system and subsequently leading to the neuronal inflammatory might related to the progression of the brain atrophy and aggravated the symptom of bipolar disorder.
Study had shown that treatment with immune-targeted therapies shown antidepressant properties. For example, open-label acetylsalicylic acid when added to fluoxetine led to increased remission rates in individuals with major depression whom were previously non-responsive to fluoxetine monotherapy (Mendlewicz, J., Kriwin, P., Oswald, P., Souery, D., Alboni, S., Brunello, N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006; 21(4): 227-31). Thus, using the anti-inflammatory agent combine with the mood stabilizer might as a potential strategy to improve the treatment effect of bipolar disorder.
Recently, mood stabilizers have been shown to activate interconnected intracellular signaling pathways that promote neurogenesis and synaptic plasticity. Remarkable progress, at present, has been made in our understanding of the actions of mood stabilizers on neuron intracellular signaling pathways.
While the underlying therapeutic mechanisms are unclear, a growing body of evidence suggests that valproate (VPA) has neuroprotective and neurotrophic actions. Remarkably, the reduction in brain volume on bipolar patients was found to be largely suppressed by chronic treatment with VPA. An increasing number of reports show that long-term administration of VPA results in neuroprotective effects. It renders neurons less susceptible to a variety of insults (Chen P S, Peng G S, Li G, et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry. December 2006; 11(12):1116-1125) and even stimulates neurogenesis in the adult rodent brain. VPA induces cytoprotective proteins like Bc1-2, glucose-regulated protein 78 (Grp78), brain-derived neurotrophic factor (BDNF) and heat shock protein 70. Moreover, VPA promotes neurite outgrowth, while VPA at therapeutic levels were reported to inhibit histone deacetylase (HDAC), an enzyme that catalyzes the removal of acetyl group from lysine residues of histones. Thus, the capability of VPA to covalently modify histone structures through enhanced acetylation may trigger changes in the expression of distinct downstream genes.